Vertebrate Paralogous MEF2 Genes: Origin, Conservation, and Evolution

BACKGROUND: The myocyte enhancer factor 2 (MEF2) gene family is broadly expressed during the development and maintenance of muscle cells. Although a great deal has been elucidated concerning MEF2 transcription factors' regulation of specific gene expression in diverse programs and adaptive responses, little is known about the origin and evolution of the four members of the MEF2 gene family in vertebrates. METHODOLOGY/PRINCIPAL FINDINGS: By phylogenetic analyses, we investigated the origin, conservation, and evolution of the four MEF2 genes. First, among the four MEF2 paralogous branches, MEF2B is clearly distant from the other three branches in vertebrates, mainly because it lacks the HJURP_C (Holliday junction recognition protein C-terminal) region. Second, three duplication events might have occurred to produce the four MEF2 paralogous genes and the latest duplication event occurred near the origin of vertebrates producing MEF2A and MEF2C. Third, the ratio (K(a)/K(s)) of non-synonymous to synonymous nucleotide substitution rates showed that MEF2B evolves faster than the other three MEF2 proteins despite purifying selection on all of the four MEF2 branches. Moreover, a pair model of M0 versus M3 showed that variable selection exists among MEF2 proteins, and branch-site analysis presented that sites 53 and 64 along the MEF2B branch are under positive selection. Finally, and interestingly, substitution rates showed that type II MADS genes (i.e., MEF2-like genes) evolve as slowly as type I MADS genes (i.e., SRF-like genes) in animals, which is inconsistent with the fact that type II MADS genes evolve much slower than type I MADS genes in plants. CONCLUSION: Our findings shed light on the relationship of MEF2A, B, C, and D with functional conservation and evolution in vertebrates. This study provides a rationale for future experimental design to investigate distinct but overlapping regulatory roles of the four MEF2 genes in various tissues

Towards a complete in silico assessment of the outcome of cochlear implantation surgery

Cochlear implantation (CI) surgery is a very successful technique, performed on more than 300,000 people worldwide. However, since the challenge resides in obtaining an accurate surgical planning, computational models are considered to provide such accurate tools. They allow us to plan and simulate beforehand surgical procedures in order to maximally optimize surgery outcomes, and consequently provide valuable information to guide pre-operative decisions. The aim of this work is to develop and validate computational tools to completely assess the patient-specific functional outcome of the CI surgery. A complete automatic framework was developed to create and assess computationally CI models, focusing on the neural response of the auditory nerve fibers (ANF) induced by the electrical stimulation of the implant. The framework was applied to evaluate the effects of ANF degeneration and electrode intra-cochlear position on nerve activation. Results indicate that the intra-cochlear positioning of the electrode has a strong effect on the global performance of the CI. Lateral insertion provides better neural responses in case of peripheral process degeneration, and it is recommended, together with optimized intensity levels, in order to preserve the internal structures. Overall, the developed automatic framework provides an insight into the global performance of the implant in a patient-specific way. This enables to further optimize the functional performance and helps to select the best CI configuration and treatment strategy for a given patient.This work was financially supported by the European Commission (FP7 project number 304857, HEAR-EU), Generalitat de Catalunya (PRODUCTE program, project number 2016PROD00047) and the Spanish Ministry of Economy and Competitiveness under the Maria de Maeztu Units of Excellence Programme (MDM-2015-0502)