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/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 agnts3 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 agnts3 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 agnts3 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 agnts3 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 agnts3 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 agnts3 making this mutant a simple plausible Drosophila model for WBS.
Highlights
Nuclear organization and 3D chromatin architecture are believed to play a main role in cognition and neuropsychiatric disorders (Medrano-Fernández and Barco, 2016).The genomic diseases representing syndromes with multiple manifestations, occur spontaneously and sporadically as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture
During the past 35 years the convergence of DNA structural biology, genetic, and genomic studies, bioinformatics, and medicine has led to a notion that in both prokaryotes and eukaryotes segments of DNA are conformationally polymorphic
They can exist in alternative non-B DNA forms, such as, cruciforms, slipped structures, triplexes, left-handed Z-DNA, and tetraplexes
Summary
Nuclear organization and 3D chromatin architecture are believed to play a main role in cognition and neuropsychiatric disorders (Medrano-Fernández and Barco, 2016).The genomic diseases representing syndromes with multiple manifestations, occur spontaneously and sporadically as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture. Among them are the Williams Beuren syndrome, Smith-Magenis syndrome, DiGeorge syndrome (Carvalho and Lupski, 2016). These syndromes occur with a frequency of 0.7– 1.0 per 1,000 live births, share neurodevelopmental phenotypes, and are detected by genome-wide segmental aneuploidy screening. Genome-wide studies of the genomic disorders have uncovered the key role of genome architecture in the formation of structural variants (SVs). Transposable genetic elements (TEs) present an example of INDELs; upon integrating they may cause DNA insertions leading to human diseases (Ostertag and Kazazian, 2001; Mullaney et al, 2010; Carvalho and Lupski, 2016). MiRNAs in the central nervous system are involved in epigenetic networks tuned by INDELs and TEs (Feschotte, 2008; Mattick, 2011; Morris and Mattick, 2014; Cao et al, 2016)
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