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PNAS Papers on Positive Epistasis in Cystic Fibrosis, Tiger Rattlesnake Genome, More

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.

For a paper slated to appear in PNAS this week, investigators in Germany, the US, and Canada describe positive epistasis between disease-causing missense mutations in the cystic fibrosis gene CFTR and a common, synonymous SNP (sSNP) in that CF transmembrane conductance regulator gene. The team scrutinized available CFTR gene or exome sequence data for thousands of individuals with cystic fibrosis, narrowing in on missense mutations and potential modifiers for further analysis in cell line experiments, ultimately landing on a sSNP that appeared to alter the translation speed associated with the causal mutation-affected codon. "Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity," the researchers report, adding that the "most robust effect was observed when the sSNP was in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon."

A team led by investigators at Clemson University shares findings from the Tiger rattlesnake (Crotalus tigris) genome, focusing on potential contributors to the snake's venom. Using a combination of short- and long-read sequencing, the researchers put together a 1.61 billion base genome assembly containing more than 18,200 predicted protein-coding genes for the C. tigris, along with corresponding RNA sequence, whole-genome bisulfite sequence, and ATAC-seq data from specific snake tissues. Along with venom-related genes, their subsequent comparisons with sequences from several other snakes pointed to gene loss events, chromatin accessibility shifts, and methylation changes related to simple venom production in the Tiger rattlesnake. "The number of venom genes greatly exceeded the number of venom proteins producing the simple phenotype, indicating regulatory mechanisms were responsible for the production of the simplest, but most toxic, rattlesnake venom," they report. "We suggest that the retention of genomic complexity may be the result of shared regulatory elements among gene-family members."

Chinese researchers report on imprinted targets for the genomic imprinting regulator ZFP57 in a mouse model, along with DNA methylation loss at imprinting control regions (ICRs) in mouse embryos missing the gene. The researchers relied on qRT-PCR, RNA sequencing, combined bisulfite restriction analyses, and other approaches to profile imprinted gene levels and DNA methylation patterns in embryos from mouse crosses involving strains missing one or both copies of the ZFP57 gene, revealing methylation loss and related shifts in the maternal and paternal alleles of imprinted gene targets in embryos lacking ZFP57. Among other things, they found that "loss of ZFP57 caused loss of parent-of-origin-dependent monoallelic expression of the target imprinted genes," and conclude that "ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs."