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Genomics in the Journals: Jan 31, 2013

NEW YORK (GenomeWeb News) – In the early, online edition of the Proceedings of the National Academy of Science, researchers from Yale University and the University of Brescia in Italy reported on protein-coding portions of the genome that are recurrently affected by somatic mutations or copy number changes in an aggressive endometrial cancer subtype called uterine serous carcinoma, or USC. Through whole-exome sequencing analyses of 57 tumors and nearly as many matched normal samples, the group characterized the somatic mutations and copy number gains or losses that tend to occur in USC. A few of the tumors contained extensive protein-coding mutations, affecting thousands of sites in the exome. But in most of the tumors, the mutational burden was more modest, researchers reported. Along with previously described cancer players such as TP53 and KRAS, they documented recurrent changes affecting the chromatin remodeling and chromatin modifying genes CHD4 and MBD3. Also mutated in multiple samples was TAF1, a gene coding for a component of the TFIID transcription factor complex.

"In addition to a number of well-known cancer genes, we found three genes that had not previously been associated with cancer that are found in these tumors," senior author Alessandro Santin, an obstetrics, gynecology, and reproductive sciences researcher at Yale, said in a statement. "This finding points to new pathways that could be important in developing therapies down the road."

A study in the American Journal of Human Genetics highlighted sites in the genome that are prone to rare-but-recurrent large copy number changes in individuals with autism. The University of Washington's Evan Eichler and colleagues from the University of Washington and the National Human Genome Research Institute used a custom array to screen for repeat-related rearrangement hotspots in 2,588 individuals with autism spectrum disorder and 580 without, focusing on hotspots associated with segmental duplications. Though they did not detect an increase in the overall number of small hotspots in the genomes of those with ASD, the investigators did see an over-representation of large, recurrent hotspots in the ASD group, including some hotspots containing smaller-than-usual CNVs — findings verified by candidate hotspot genotyping in thousands more unaffected controls. In addition to finding sets of genes that tended to be recurrently affected by CNVs in ASD, the team also defined certain ASD features that seem to coincide with the nature and size of CNVs carried by an individual.

"We found that as the size of deletions increases, non-verbal IQ significantly decreases, but there is no impact on autism severity," Eichler and his co-authors reported, "and as the size of duplications increases, autism severity significantly increases, but non-verbal IQ is not affected.

"The absence of an increased burden of smaller CNVs in autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state," they added.

Gut microbial communities may contribute to the risk of kwashiorkor — a severe form of acute malnutrition characterized by wasting, appetite loss, and a swollen abdomen as well as skin and liver problems — according to a new study in Science. An international team led by Washington University in St. Louis investigators collected fecal samples from 317 pairs of twins from Malawi between infancy and the age of three. Over their first three years, half of the twin pairs remained healthy, while 7 percent developed some form of malnutrition that affected both twins.

For 43 percent of twin sets, though, researchers saw a situation in which one twin was malnourished while the other was not. To explore this in more detail, the team used metagenomic sequencing to assess gut microbiomes in a subset of the healthy twin pairs and pairs discordant for the kwashiorkor form of malnutrition. Results of the analyses indicated that gut communities in children with kwashiorkor did not show the same steady shift towards the more mature microbiome composition that was detected in healthy children, even after malnourished children received therapeutic food designed to treat kwashiorkor. Moreover, the team saw notable weight loss in germ-free mice transplanted with fecal samples from the Malawian co-twins with kwashiorkor, suggesting metabolic features of the microbiome itself can influence malnutrition.

"These findings suggest that energy metabolism may be a bigger challenge for these children when they are exposed to a nutrient-deficient, low-calorie diet," senior author Jeffrey Gordon, with Washington University's Center for Genome Sciences and Systems Biology, said in a statement.

"We hope that these studies will provide a new way of understanding how the gut microbiome and food interact to affect the health and recovery of malnourished children," he added.

A Cornell University-led team took a look at changes in DNA methylation across the tomato genome during the fruit ripening process for a study published in Nature Biotechnology this week. The researchers used bisulfite sequencing and other approaches to define DNA cytosine methylation patterns genome-wide across several stages of tomato development. In the process, they uncovered almost 52,100 regions of the genome that showed shifts in their DNA methylation profiles during ripening. Among them, they noted, were demethylated regions that overlapped with sites bound by ripening-related transcription factors.

"Our data show that the epigenome is not static during development and may have been selected to ensure the fidelity of developmental processes such as ripening," senior author James Giovannoni, a researcher affiliated with Cornell University's Boyce Thompson Institute for Plant Research and the US Department of Agriculture-Agriculture Research Service, and colleagues wrote.

"Crop-improvement strategies could benefit by taking into account not only DNA sequence variation among plant lines," they added, "but also the information encoded in the epigenome."

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