CHARACTERIZATION OF THE EUKARYOTIC TRANSLATION INITIATION FACTOR 4E (eIF4E) FAMILY MEMBERS IN THE ZEBRAFISH (Danio rerio)

The present study examines the six eIF4E cognates in zebrafish. In addition to the prototypical translation initiation factor eIF4E, eukaryotes have evolved eIF4E variants with distinct characteristics, some of which negatively regulate the recruitment of specific mRNAs. Metazoan eIF4E family members fall into three classes, with Class I containing the canonical translation initiation factor eIF4E-1. eIF4E-1 binds eIF4G to initiate translation, a process inhibited by eIF4E binding proteins such as the 4E-BPs and other eIF4E interactive proteins. Analysis of eIF4E sequences from the twenty fish genomes currently available, as well as those of echinoderm, tunicate and cephalocordate, has allowed a glimpse of the origins and evolution of the eIF4E family in vertebrates. All deuterostomes have one representative from each class of eIF4Es. Early deuterostomes such as sea urchins, tunicates, and lancelets have only one from each class; eIF4E-1, eIF4E-2 and eIF4E-3. The distribution of the subclasses of eIF4E-1 is consistent with the duplication of Class I prior to the teleost specific whole genome duplication, probably at one of the whole genome duplications at ~550 (1R) and 500 (2R) mya. Evidence of the duplication of Class I eIF4Es can be seen in elephant shark (Callorhinchus milii), coelacanth (Latimeria chalumnae) and basal ray-finned fish (Lepisosteus oculatus), which have eIF4E-1A, -1B, and -1C. eIF4E-1B has neofunctionalized to become a tissue specific regulator of mRNA recruitment. It has been retained in tetrapods, but lost in higher teleosts. eIF4E-1C, appears to have retained function as a prototypical initiation factor. A duplication of Class II eIF4Es occurred prior to the emergence of the tetrapod branch, becoming eIF4E-2A and -2B. The genes proximal to the eIF4E-2A locus appear to be conserved across teleosts and tetrapods, the eIF4E-2B genetic loci are more variable, suggesting that eIF4E-2A is the ancestral form. eIF4E-2B is retained by amphibians and teleosts, but has been lost in coelacanth and amniotes. Although 88 % identical, eIF4E-2B can be distinguished from eIF4E-2A by its ability to bind trimethyl GTP (TMG) and to complement a S. cerevisiae strain conditionally deficient in eIF4E. This study has shown that duplication within the different classes of eIF4E occurred early in vertebrate evolution with some neofunctionalization, as well as asymmetric losses in different vertebrate classe

Unravelling the roles of susceptibility loci for autoimmune diseases in the post-GWAS era

Although genome-wide association studies (GWAS) have identified several hundred loci associated with autoimmune diseases, their mechanistic insights are still poorly understood. The human genome is more complex than single nucleotide polymorphisms (SNPs) that are interrogated by GWAS arrays. Apart from SNPs, it also comprises genetic variations such as insertions-deletions, copy number variations, and somatic mosaicism. Although previous studies suggest that common copy number variations do not play a major role in autoimmune disease risk, it is possible that certain rare genetic variations with large effect sizes are relevant to autoimmunity. In addition, other layers of regulations such as gene-gene interactions, epigenetic-determinants, gene and environmental interactions also contribute to the heritability of autoimmune diseases. This review focuses on discussing why studying these elements may allow us to gain a more comprehensive understanding of the aetiology of complex autoimmune traits.</p