Genomic analysis of Fmr1 cluster: possible implications in Fragile-X associated diseases

MARINA LUZ INGRAVIDI; IANINA FERDER; LILIANA DAIN; LAURA KAMENETZKY

Simposio; Student Council Symposium; 2022

Background:The Fragile X Mental Retardation-1 (FMR1) gene consists of 17 exons spanning 38 kb of the Xq27.3 chromosome and codes for the protein fragile X mental retardation protein (FMRP). FMR1 is involved, by different molecular mechanisms, in 3 genetic disorders. Recently, a microRNA (miRNA) cluster adjacent to FMR1 (Fx-mir) has been described in placental mammals and it has been shown that a number of miRNAs in the cluster target FMR1 in human and mouse, regulating its expression. In this work, we described the Fx-mir cluster and the putative targets of its miRNAs in Rattus norvegicus (rat). In particular, we were interested in studying whether some of the Fx-mir miRNAs target Fmr1 in the rat as well.Description:We used public databases and performed a reciprocal best hit sequence identity analysis using the human Fx-mir miRNAs as bait in order to find orthologous miRNAs in the rat. We found a total of 18 miRNAs located in the Fx-mir cluster in rat. Among these miRNAs, 8 have a conserved seed region and chromosome location in both species.Next, to study putative targets of Fx-mir miRNAs, we searched for miRNAs predicted to target Fmr1 using the gene of interest as input in specialized target finding softwares. We also made an additional search, finding every possible target for each miRNA of Fx-mir. We found that miR-880 is a possible regulator of Fmr1. We extended the search to all the X chromosome, finding 8 more candidates predicted to target Fmr1 that might be of interest. Finally, we performed a genomic synteny analysis using MAUVE, in order to identify conserved regions within Fx-mir.Conclusions:We found low sequence identity between rat and human Fx-mir/FX-MIR regions. Nonetheless, the genomic regions maintain a structural and evolutionary conservation. Most Fx-mir/FX-MIR miRNAs belong to the MIR-506 family. Finally, we obtained some miRNA sequences that could potentially target and regulate Fmr1 in our study model, sequences whose expression will be analyzed in our laboratory.