The distribution of fitness effects among synonymous mutations in a gene under directional selection.

The fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitness effects among synonymous mutations for a gene under directional selection and capable of adapting via synonymous nucleotide changes. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. A positive correlation between fitness and the presence of synonymous substitutions across a phylogeny of related Pseudomonads suggests these mutations may be common in nature. Taken together, our results provide the most compelling evidence to date that synonymous mutations with non-neutral fitness effects may in fact be commonplace.

Impact of Intestinal Ultrasound on Classification and Management of Crohn's Disease Patients with Inconclusive Colonoscopy.

Background and Aims. We aim to evaluate the benefit of ultrasound in the assessment of Crohn's disease and to demonstrate its potential contribution to disease management. Methods. We conduct a retrospective review of adult patients with Crohn's disease examined with sonography and colonoscopy within 30 days. Study patients were identified in whom colonoscopy did not access a pathological segment, detected and evaluated by ultrasonography. Changes in management were predominantly attributed to ultrasound in those cases where the diseased segment was not assessed on endoscopy. Results. From 115 patients with temporally related ileocolonoscopy and ultrasound, 41 had disease fully assessed on ultrasound only, with complications in 26/41. Twenty-nine of 41 had mild or no endoscopic inflammation with moderate or severe disease on ultrasound at the same segment or at a segment proximal to the reach of the endoscope. Changes in management were significantly attributed to ultrasound in 22 of these 29 patients. Conclusion. The benefit of cross-sectional imaging is invaluable for the comprehensive assessment of bowel not shown on ileocolonoscopy. Ultrasound may make a significant contribution to correct classification of disease extent and severity of Crohn's disease. Prospective studies are needed to further understand the contribution of US in patient management.