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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/ mariner  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  Drosophila melanogaster  mutant  agn   ts 3  has unusual architecture of the  agnostic  locus harboring  LIMK1 : it is a hotspot of chromosome breaks, ectopic contacts, underreplication, and recombination. Here, we present the analysis of  LIMK1 -containing locus sequencing data in  agn   ts 3  and three  D. melanogaster  wild-type strains— Canton-S, Berlin , and  Oregon-R . We found multiple strain-specific SVs, namely, single base changes and small INDEls. The specific feature of  agn   ts 3  is 28 bp A/T-rich insertion in intron 1 of  LIMK1  and the insertion of mobile S-element from Tc1/ mariner  superfamily residing ~460 bp downstream  LIMK1  3′UTR. Neither of SVs leads to amino acid substitutions in  agn   ts 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  agn   ts 3  relative to the wild-type strains. Thus,  LIMK1  DNA structure  per se , as well as the pronounced changes in total miRNAs profile, probably lead to  LIMK1  dysregulation and complex behavioral dysfunctions observed in  agn   ts 3  making this mutant a simple plausible  Drosophila  model for WBS.

frontiers in genetics

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