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This Week in PNAS: Mar 8, 2016

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

In the early, online edition of the Proceedings of the National Academy of Sciences, researchers from the University of Hong Kong and elsewhere describe mutations in the macrophage-stimulating receptor 1 gene MST1R that seem to increase risk of nasopharyngeal carcinoma in individuals of Southern Chinese descent. The team tracked down the MST1R association through gene-based analyses on exome sequence data from 161 Southern Chinese individuals with nasopharyngeal carcinoma and 895 unaffected controls from the same population, particularly amongst individuals who developed the disease before the age of 20 years old. The authors verified ties between nasopharyngeal carcinoma and germline changes to MST1R in another 2,160 cases and 2,433 controls before delving further into the biological basis of the association.

A team from the Netherlands reports on findings from a screen aimed at analyzing variants of unknown significance to find pathogenic DNA mismatch repair (MMR) gene mutations involved in Lynch syndrome, a condition marked by increased risk of cancers such as early onset colorectal cancer. Using oligonucleotide-directed mutagenesis in mouse embryonic stem cells, the researchers screened dozens of variants of unknown significance in the mutator S homolog 2 gene MSH2, uncovering 19 changes to the gene that were deemed pathogenic. "[W]e demonstrate that gene modification by short [single-stranded oligodeoxyribonucleotides] can be used to efficiently fulfill a specific clinical need: the functional interrogation of variants of DNA MMER genes to establish whether they are causative for [Lynch syndrome]," the authors write.

Columbia University researchers present an algorithm designed to detect genetic variants that impact networks of transcription factors and their target genes. In its proof-of-principle experiments, the team used the transcription factor-centric computational method to predict connectivity quantitative trait loci for more than 100 Saccharomyces cerevisiae segregants made by crossing a lab strain and a strain from a California vineyard, based on genome-wide gene expression data and genotyping information at nearly 3,000 chromosomal loci. The search led to a DIG2 gene mutation that appeared to tinker with connectivity of the Ste12p transcription factor, for example, as well as TAF13 gene variants suspected of influencing Gcn4p transcription factor activity.