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Genomics in the Journals: Mar 21, 2013

NEW YORK (GenomeWeb News) – In Nature Genetics, an international team led by investigators in France described findings from a genome-wide association study of pulmonary arterial hypertension, a progressive high blood pressure disease that's due, in part, to vascular cell proliferation in some small pulmonary arteries.

For the discovery and replication stages of the study, the researchers focused on 625 individuals with either familial or idiopathic pulmonary arterial hypertension. None of the cases carried detectable mutations to a gene called BMPR2, which has been implicated in some pulmonary arterial hypertension cases in the past.

Through comparisons between SNP profiles in affected individuals and genotyping data on 1,525 unaffected controls, investigators narrowed in on a previously unappreciated pulmonary arterial hypertension-associated locus on chromosome 18 that appears to almost double the risk of the rare disease. The closest gene, CBLN2, is typically expressed in lung tissue, the team found in its follow-up experiments. And consistent with a possible role for CBLN2 in pulmonary arterial hypertension, the gene's expression was particularly pronounced in lung samples from those with pulmonary arterial hypertension.

"Fine mapping and deep sequencing of the entire locus is now required to identify and characterize the functional variant(s) responsible for the observed association," researchers wrote. "These results pave the way for improved understanding of pathophysiology as well as new therapeutic approaches for [pulmonary arterial hypertension]."

The set of genetic variants implicated in inflammatory disease risk includes an over-representation of variants stemming from sites in the genome influenced by positive selection, according to a study in the American Journal of Human Genetics. Researchers with Brigham and Women's Hospital, the University of Chicago, and elsewhere took a systems-based approach to assessing hundreds of SNPs linked to inflammatory disease through past GWAS.

Starting from more than 400 inflammatory disease-related SNPs, the investigators found risk variants at 21 loci that fell in parts of the genome with signs of recent positive selection. Not only are proteins within these selected regions particularly apt to interact with one another, they reported, but more than a dozen of the inflammatory-linked loci within the selection-affected sites exhibited ties to the expression of nearby genes.

"The results presented here provide support for recent positive selection having shaped a portion of genetic variation in influencing inflammatory-disease susceptibility to a greater extent than genetic variation associated with other common diseases," co-senior authors Philip De Jager, with BWH, and Barbara Stranger, from the University of Chicago, and their colleagues wrote.

"The core selected network contains genes that influence susceptibility to multiple different diseases and may be critical to setting the likelihood of responses to self-antigens," they added, "whereas disease-specific susceptibility loci may play a greater role in the syndromic manifestations of an immune reaction against self."

A collection of review articles in Cell examined a range of issues revolving around a nuclear dynamics theme — from genomic regulation and organization to the molecular interactions that delineate the nucleus and control entry into the organelle.

For instance, the University of Edinburgh's Wendy Bickmore, together with Bas van Steensel from the Netherlands Cancer Institute, discussed research related to genome architecture — namely, the factors influencing chromosomes' three-dimensional orientation and organization during the interphase portion of the cell cycle. Other review articles tackled topics that included gene splicing and regulation, imprinting and epigenetics, and long non-coding RNAs.

In the same issue, meanwhile, European Molecular Biology Laboratory genome biology researcher Jan Korbel and Peter Campbell, a cancer genome researcher with the Wellcome Trust Sanger Institute and the University of Cambridge, presented a primer on the type of evidence needed to accurately attribute chromosomal rearrangement in cancer genomes to chromothripsis.

A study in Science suggests that pigmentation patterns on fruit fly wings are the consequence of numerous pigmentation gene networks orchestrated by transcriptional regulators that act on specific sets of these genes.

In an effort to tease apart some of the processes involved in morphological evolution within related species, French researchers focused on a wing color pattern found in some fruit flies that's characterized by a splotch of dark pigmentation. Starting from expression analyses of a gene called yellow, which is a known player in black pigmentation patterns, they went on to use an RNA interference screen to untangle the regulatory networks behind the black wing spot pattern.

Their analysis indicated that pigmentation-related regulatory modules likely evolved through new interactions between transcriptional regulators and certain pigmentation-related genes, producing previously unlinked regulatory modules.

"These results suggest that the genetic changes underlying the emergence and diversification of wing pigmentation patterns are partitioned within genetic networks," the study authors said.

More broadly, they explained, the hint that "morphological novelties may result from the evolutionary modifications of effector genes, whereas their spatial diversification involves the redeployment of upstream patterning genes."

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