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PNAS Papers on GWAS False Discovery, PRAMEF2 Role in Tumorigenesis, RNA Virus Reverse Genetics

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

A team from the University of Southern California, the University of California, Berkeley, and Stanford University outlines a computational strategy to account for false discovery rates (FDR) in genome-wide association studies — a statistical framework the group applied to simulated data and to data from the UK Biobank project. Rather than evaluating a phenotype of interest against individual variables in a linear method, the researchers say, the new software simultaneously evaluates all variants to take genotype randomness into account with the help of population structure insights. "Our solution accounts for linkage disequilibrium and population structure, controls the false discovery rate, and leverages powerful machine-learning tools," they write.

For another paper slated to appear in PNAS this week, researchers at the National Institute of Immunology in New Delhi dig into an apparent role for the cancer testis antigen PRAMEF2 in the development of several cancer types. From promoter sequence data, protein expression and interaction experiments, and other cell biology analyses, the team saw signs that PRAMEF2 contributes to tumorigenesis via the Hippo/YAP signaling pathway, by regulating polyubiquitylation and related degradation of a kinase enzyme called LATS1. "[L]ATS1 degradation promotes enhanced nuclear accumulation of the transcriptional co-activator YAP, resulting in increased expression of proliferative and metastatic genes," the authors report, adding that "elevated PRAMEF2 levels correlate with increased nuclear accumulation of YAP in advanced grades of breast carcinoma."

Investigators at Osaka University, Yamaguchi University, and Japan's National Institute of Infectious Diseases describe a reverse genetics system used for assessing double-stranded RNA viruses from the Coltivirus genus, including the Tarumizu tick virus, the Colorado tick fever virus, and other members of the Reoviridae family. The team came up with a plasmid-based system representing a Tarumizu tick virus (TarTVs) by cloning complementary DNAs spanning all 12 genome segments of a TarTV isolate found in a deceased raccoon dog brain. The recombinant TarTVs, including mutant and reporter versions of the virus, were then tested in baby hamster kidney cell, the authors explain, noting that the reverse genetics system "provides opportunities for understanding the mechanisms of replication and pathogenesis of viruses within the genus Coltivirus."