Drosophila Model for the Analysis of Genesis of LIM-kinase 1-Dependent Williams-Beuren Syndrome Cognitive Phenotypes: INDELs, Transposable Elements of the Tc1/Mariner Superfamily and MicroRNAs

Abstract

Genomic disorders, the syndromes with multiple manifestations, may occur sporadically due to unequal recombination in chromosomal regions with specific architecture. Therefore, each patient may carry an individual structural variant of DNA sequence (SV) with small insertions and deletions (INDELs) sometimes less than 10 bp. The transposable elements of the Tc1/<i>mariner</i> superfamily are often associated with hotspots for homologous recombination involved in human genetic disorders, such as Williams Beuren Syndromes (WBS) with LIM-kinase 1-dependent cognitive defects. The <i>Drosophila melanogaster</i> mutant <i>agn</i>^<i>ts</i>3 has unusual architecture of the <i>agnostic</i> locus harboring <i>LIMK1</i>: it is a hotspot of chromosome breaks, ectopic contacts, underreplication, and recombination. Here, we present the analysis of <i>LIMK1</i>-containing locus sequencing data in <i>agn</i>^<i>ts</i>3 and three <i>D. melanogaster</i> wild-type strains-<i>Canton-S, Berlin</i>, and <i>Oregon-R</i>. We found multiple strain-specific SVs, namely, single base changes and small INDEls. The specific feature of <i>agn</i>^<i>ts</i>3 is 28 bp A/T-rich insertion in intron 1 of <i>LIMK1</i> and the insertion of mobile S-element from Tc1/<i>mariner</i> superfamily residing ~460 bp downstream <i>LIMK1</i> 3'UTR. Neither of SVs leads to amino acid substitutions in <i>agn</i>^<i>ts</i>3 LIMK1. However, they apparently affect the nucleosome distribution, non-canonical DNA structure formation and transcriptional factors binding. Interestingly, the overall expression of miRNAs including the biomarkers for human neurological diseases, is drastically reduced in <i>agn</i>^<i>ts</i>3 relative to the wild-type strains. Thus, <i>LIMK1</i> DNA structure <i>per se</i>, as well as the pronounced changes in total miRNAs profile, probably lead to <i>LIMK1</i> dysregulation and complex behavioral dysfunctions observed in <i>agn</i>^<i>ts</i>3 making this mutant a simple plausible <i>Drosophila</i> model for WBS.