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Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology. [ABSTRACT FROM AUTHOR]

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (Na V 1.7), SCN10A (Na V 1.8), and SCN11A (Na V 1.9) in patients with painful and nonpainful peripheral neuropathy., Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful)., Results: We identified 36 ( SCN9A ), 31 ( SCN10A ), and 15 ( SCN11A ) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A , there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations., Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of Na V 1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease "mutations," are more important for the development of painful neuropathy than previously discussed.

How many species inhabit our immediate surroundings? A straightforward collection technique suitable for answering this question is known to anyone who has ever driven a car at highway speeds. The windshield of a moving vehicle is subjected to numerous insect strikes and can be used as a collection device for representative sampling. Unfortunately the analysis of biological material collected in that manner, as with most metagenomic studies, proves to be rather demanding due to the large number of required tools and considerable computational infrastructure. In this study, we use organic matter collected by a moving vehicle to design and test a comprehensive pipeline for phylogenetic profiling of metagenomic samples that includes all steps from processing and quality control of data generated by next-generation sequencing technologies to statistical analyses and data visualization. To the best of our knowledge, this is also the first publication that features a live online supplement providing access to exact analyses and workflows used in the article.