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Genomics In The Journals: Nov 21, 2012

NEW YORK (GenomeWeb News) – Through a genome-wide association study, researchers identified two candidate genes for susceptibility to nonsyndromic sagittal craniosynostosis, which they reported in an advance online article in Nature Genetics this week. Craniosynostosis occurs when the bones of the skull fuse too early during human development, leading to neurological and visual problems as well as learning disabilities due to ensuing brain compression.

While about 20 percent of craniosynostosis cases occur in conjunction with other syndromes, most do not. For their GWAS, researchers led by Simeon Boyadjiev, a professor of pediatrics and genetics at the University of California, Davis, focused on a non-syndromic form of craniosynostosis affecting the sagittal suture of the skull. This form of craniosynostosis, called sNSC, affects about 1 in 5,000 infants, though it is more common in boys than in girls, and it appears to have a genetic basis as identical twins are more likely to both be affected than fraternal twins are.

To search for susceptibility loci for sNSC, the researchers genotyped 130 case-parent trios of non-Hispanic European ancestry. They uncovered 21 SNPs on two chromosomes that reached genome-wide significance.

The 18 SNPs on chromosome 20 were in two linkage disequilibrium blocks, and the researchers noted that the most significant SNP was just downstream of the gene BMP2. In addition, the three SNPs on chromosome 7 were within introns of the gene BBS9. Both BMP2 and BBS9 have known associations with skeletal development.

The researchers then focused on the 104 trios with a male proband, and the same 21 SNPs reached genome-wide significance; another marker had a low p-value, but it did not reach the level of significance.

The findings were replicated in separate study of 172 unrelated cases and 548 controls.

"No matter how we analyzed the data ― whether we included familial cases, cases with other minor anomalies, or mixed children of different ethnic groups together, these two genetic factors were highly significant," said Boyadjiev in a statement. "This provides strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate."

A newly isolated human coronavirus is closely related to coronaviruses found in bats, according to a genomic characterization of the virus published in mBio this week. The virus, called HCoV-EMC/2012, was isolated from a man in Saudi Arabia who died in June after developing acute respiratory distress syndrome and multiple organ dysfunction syndrome.

The international team of researchers led by Ron Fouchier, a virologist at the Erasmus Medical Center in The Netherlands, used an optimized random-amplification deep-sequencing approach to cover about 90 percent of the viral genome. From that, it developed primers to use for conformational Sanger sequencing.

The group recently presented a case report in the New England Journal of Medicine describing how it isolated the virus.

In this paper, the research team reported that HCoV-EMC/2012 contains 30,119 nucleotides and about 10 predicted open-reading frames. In addition, from its phylogenetic analysis of the coronavirus replicase gene, it noted that HCoV-EMC/2012 is most closely related to the BtCoV-HKU4 and BtCoV-HKU5 coronaviruses that were first found in bats from Asia, including in a bat species known to live in Saudi Arabia. According to the team, these findings suggest that HCoV-EMC/2012 may have emerged from bats.

Further, they said that HCoV-EMC/2012 is distinct enough from its closest relatives to be a new species of coronavirus, and the first in its lineage known to infect humans.

Using a chemogenomic approach, researchers from Cornell University identified a previously unknown enzyme that catalyzes the last step in the diphthamide synthesis pathway, as they reported in the Proceedings of the National Academy of Sciences this week. Diphthamide, the researchers noted, was discovered more than 30 years ago, and the enzyme catalyzing the amidation step remained elusive all the while.

The researchers drew on data contained in the Yeast Fitness database, which catalogues the growth fitness of about 5,000 Saccharomyces cerevisiae strains with various gene deletions and how those strains respond to a number of small molecules and other stresses. They hypothesized that strains without the diphthamide synthetase gene would have similar cofitness scores with strains lacking other parts of the diphthamide synthesis pathway. From this, the researchers determined that a gene related to the yeast YBR246W was likely involved in the pathway, and they noted that strains lacking YLR143W had a higher cofitness value to other strains lacking known diphthamide synthesis pathway genes.

Through Blast, the researchers further homed in on YLR143W, which is conserved in eukaryotes and bacteria. They then, by studying and rescuing strains lacking YLR143W, confirmed that YLR143W catalyzes the final step of the diphthamide synthesis pathway.

"We have shown that the cofitness data are powerful in discovering missing members in a biosynthetic pathway," the researchers wrote.

Cancer cells develop a number of mutations, some of which allow them to be resistant to cancer drugs. MED12 may be a biomarker to gauge response to a number of cancer drugs, researchers from The Netherlands and Agendia reported in Cell this week. MED12 makes up part of the MEDIATOR transcriptional adaptor complex that connects transcription machinery to its activators.

To find genes involved in drug resistance, the researchers performed an RNAi screen using 24,000 short hairpin RNA vectors targeting 8,000 human genes in a non-small cell lung cancer cell line containing the EML4-ALK translocation. From this, they found that MED12 suppression confers resistance to crizotinib, an ALK inhibitor. Additionally, they found that MED12 suppression leads to resistance to the EGFR inhibitors gefitinib and erlotinib.

The researchers further showed that MED12, in addition to its MEDIATOR duties, negatively regulates TGF-βR2 to activate TGF-β signaling. The TGF-βR protein plays a role in cell growth and cell death.

Finally, the researchers showed that by inhibiting TGF-β signaling in cells lacking MED12, they could restore susceptibility to cancer therapies. "We have shown that blocking this escape route restores sensitivity to the original drug, suggesting a way to treat patients that have undergone this type of drug resistance," René Bernards, from the Netherlands Cancer Institute and Agendia, said in a statement.

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

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