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Genomics in the Journals: Sep 26, 2013

NEW YORK (GenomeWeb News) – A new Nature Genetics study has implicated the receptor-ligand cadherin genes DCHS1 and FAT4 in cerebral cortex development in mammals.

An international team led by investigators in Germany and New Zealand did array-based autozygosity mapping and targeted sequencing in members of several families affected by Van Maldergem syndrome, or VMS. The autosomal recessive condition represents one form of periventricular neuronal heterotopia, a condition that occurs when developmental processes in the brain go awry, allowing cortical neurons to turn up at unusual locations.

Researchers initially tracked down suspicious changes to DCHS1 in four individuals with VMS from three different families. Their subsequent exome sequencing experiments on an individual with sporadic VMS uncovered mutations affecting FAT4, which encodes a receptor for the DCHS1 gene product.

Exome and targeted sequencing in individuals from other VMS-affected families unearthed more FAT4 mutations. Meanwhile, the group's follow-up experiments indicated that dialing down DCHS1 and FAT4 expression in developing mice leads to atypical neuronal development in the neocortex region of the mouse brain.

Still, study authors noted, the latter effect was not found in mice designed to have lower-than-usual levels of a transcriptional effector regulated by DCHS1 and FAT4, highlighting a potential role for a signaling pathway downstream of DCHS1 and FAT4 in mammalian neuronal development.

A team from the University of California at San Francisco, Albert Einstein College of Medicine, and the University of Illinois at Urbana-Champaign published a study in Nature illustrating the potential of using genomic information and structural data to tease apart metabolic pathways and corresponding enzyme players.

Using a "metabolite docking" method that draws on predicted or experimentally determined three-dimensional protein structure information, the researchers were able to uncover interacting partners for enzymes encoded by a cluster of genes in the marine bacterial species Pelagibaca bermudensis, for instance.

Taking that a step further, they found that it was possible to correctly predict the in vitro activity of known and previously uncharacterized enzymes, while defining details about metabolic pathways they belong to — results that they confirmed through additional metabolomic, genetic, and transcriptomic profiling experiments in the lab.

Researchers from the University of Vienna and the Medical University of Vienna used a combination of exome sequencing, array-based copy number profiling, fluorescence in situ hybridization, and immunohistochemistry experiments to dig up new genetic glitches contributing to the development of gastrointestinal stromal tumors — an analysis that they described in the journal Clinical Cancer Research.

In an effort to track down genes affected by gains and losses previously described in the gut cancer — and to uncover other clinically relevant genetic contributors to the condition — the team sequenced protein-coding sequences in matched tumor-normal samples from 13 individuals with GIST.

Within the broader set of 174 GIST tumors available to them, the investigators looked at copy number patterns in tumors from 29 patients. They also did FISH- and immunohistochemistry-based assessments of 125 tumors and 145 tumors, respectively.

Bringing together this data, the group found more than three-dozen genes that were altered in three or more of the GIST tumors. With the help of additional analyses, the researchers whittled that set down to 10 new genes that appear to contribute to GIST, including several genes coding for components in the MAP kinase signaling pathway.

In Molecular Biology and Evolution, researchers from France, the US, and Uzbekistan presented genetic evidence pointing to human population expansions that appear to have predated the Neolithic age, a period beginning roughly 10,000 years ago that was marked by an increasing reliance on agriculture and a flurry of plant and animal domestication.

The team assessed 20 non-protein-coding sites in the nuclear genome and markers found in hyper-variable segments of the mitochondrial genome in 66 African or Eurasian individuals, using variant patterns at these sights to try to sniff out historical information on farming, herding, and hunter-gathering groups from various geographical regions.

Based on both the polymorphism patterns they saw and the available archeological information, for instance, the study's authors speculated that human population expansions may have occurred prior to the emergence of agricultural and herding-based lifestyles — perhaps as far back as 60,000 to 80,000 years ago during the Paleolithic era.

"Human populations could have started to increase in Paleolithic times," first author Carla Aimé, an economic anthropology and ethnobiology researcher at the University of Paris, said in a statement, "and strong Paleolithic expansions in some populations may have ultimately favored their shift toward agriculture during the Neolithic."

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